Gluconeogenesis is the synthesis of glucose from non-carbohydrate precursors. Gluconeogenesis is a universal pathway found in all animals, plants, fungi, and microorganisms.
Site of gluconeogenesis
In higher animals, gluconeogenesis occurs in the liver and to a lesser extent in the kidney cortex. Eventually, under normal circumstances, the liver is responsible for 85% to 95% of the glucose that is made. However, during starvation or during metabolic acidosis the kidney is capable of making glucose and then may contribute up to 50% of the glucose formed. In these conditions, the amount contributed by the liver decreases considerably.
Precursors of gluconeogenesis:
Gluconeogenetic precursors include:
- Glycolic products like lactate pyruvate glycerol
- Citrix acids cycle intermediates
- Some amino acids termed glucogenic amino acids. Lysine and leucine are the only amino acids that are not substrates for gluconeogenesis. These amino acids produce only acetyl Co-A upon degradation.
Animal cells can carry out gluconeogenesis from three and four carbon precursors but not from the two acetyl carbons of acetyl Co-A. Animal cells also have no way to convert acetyl Co-A to pyruvate or oxaloacetate. Thus fatty acids are not substrates for gluconeogenesis in animals because most fatty acids yield only acetyl Co-A upon degradation. Unlike animals plants and some microorganisms can convert acetyl Co-A derived from fatty acid oxidation to glucose.
Although glycolysis and gluconeogenesis share several steps these pathways are not simply the reverse of each other. During gluconeogenesis seven steps are catalyzed by the same enzymes used in glycolysis, these are reversible. Three steps in glycolysis are irreversible.
These Irreversible steps are
- Conversion of glucose to glucose 6 phosphate catalyzed by hexokinase.
- The conversion of fructose-6-phosphate to 1,6-bisphosphate by phosphofructokinase (PFK- 1).
- The conversion of phosphoenolpyruvate to pyruvate by pyruvate kinase.
Conversion of pyruvate to phosphoenolpyruvate:
Pyruvate cannot be converted directly to phosphoenolpyruvate. The conversion requires two reactions that serve to bypass the irreversible pyruvate kinase step of glycolysis. The energy barrier in phosphorylating pyruvate to form phosphoenolpyruvate requires the expenditure of two high energy phosphate bonds.
For bypassing pyruvate kinase is the conversion of pyruvate to oxaloacetate, catalyzed by pyruvate carboxylase. This reaction occurs in the mitochondrial matrix.
Pyruvate carboxylase is a mitochondrial allosteric enzyme. The prosthetic group of the enzyme is biotin. Here in biotin functions as carbon dioxide carrier. Biotin is covalently bonded to the enzyme by an amide linkage between the carboxylic group of its side chain and the amino group of an enzyme lysine residue to form a biocytin. The enzyme also requires both magnesium and manganese ions for activity. Acetyl Co-A acts as an allosteric activator of pyruvate carboxylase
For bypassing pyruvate kinase is the conversion of oxaloacetate to oxaloacetate to phosphoenolpyruvate. This reaction is catalyzed by Mn2+-requiring phosphoenolpyruvate carboxykinase.
Cellular location of phosphoenolpyruvate carboxykinase
Pyruvate carboxylase is found only in the matrix of mitochondria. By contrast, phosphoenolpyruvate carboxykinase may be localized in the cytosol or in the mitochondria or both. In humans, phosphoenolpyruvate carboxykinase is found in both the mitochondria and cytosol. However, in rat and mouse liver, it is only present in the cytosol. In chickens, pigeons, and rabbits it is purely mitochondrial.
In organisms where phosphoenolpyruvate carboxylase kinase occurs only in mitochondria, oxaloacetate is converted to phosphoenolpyruvate. Phosphoenolpyruvate travels to the cytosol for gluconeogenesis. However, in organisms where oxaloacetate is converted into phosphoenolpyruvate in the cytosol, a problem arises.
Oxaloacetate cannot cross the mitochondrial membrane because the mitochondria membrane has no transporter for oxaloacetate. So oxaloacetate first reduces to malate by mitochondrial enzyme malate dehydrogenase at the expense of NADH.
Malate leaves the mitochondria through a specific transporter in the inner mitochondrial membrane and in the cytosol, it is reoxidized to oxaloacetate, with the production of cytosolic NADH.
Conversion of phosphoenolpyruvate to glucose
This pathway is the opposite of glycolysis. However, one step in the glycolytic pathway where phosphofructokinase-1 (PFK-1) is involved is irreversible. So during gluconeogenesis enzyme, Fructose-1,6-bisphosphatase acts without using ATP and converts Fructose-1,6-bisphosphate to Fructose-6-phosphate.
Fructose-1,6-bisphosphatase is an allosterically regulated enzyme. Citrate stimulates bisphosphatase activity but fructose-2,6bisphosphate is a potent allosteric inhibitor. AMP also inhibits the bisphosphatase.
Another step where glucose is converted into glucose-6-phosphate during glycolysis is catalyzed by hexokinase and requires ATP. This reaction is also irreversible. During gluconeogenesis conversion of glucose-6-phosphate to glucose requires glucose-6-phosphatase and no ATP is required. This enzyme is present in the membrane of the Endoplasmic reticulum of liver and kidney cells but is absent in muscle and brain. For this reason, gluconeogenesis does not occur in muscle and brain.
Energetics of the gluconeogenic pathway
2 Pyruvate + 2NADH + 4ATP + 2GTP + 6H2O — > Glucose + 2NAD+ + 2GDP + 4ADP + 6 Pi + H+
Glucose alanine cycle
Pyruvate formed during glycolysis in muscle can undergo transamination with glutamate to yield alanine. Alanine is transported to the liver. In the liver, alanine transaminase with Alpha-ketoglutarate to yield glutamate and pyruvate. The pyruvate is used to produce glucose by the gluconeogenetic pathway.
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